The FAS, FAS ligand (FASL), and CASP8 are key regulators for apoptosis and their deregulations play an important role in carcinogenesis. However, the effects of promoter polymorphisms of the FAS, and FASL, and CASP8 genes on the survival of gastric cancer are unknown. In this study, we investigated the association of four polymorphisms (FAS −1377G > A, −670A > G, FASL −844C > T, and CASP8 −652 6N ins > del) with the clinical outcome of 940 gastric cancer patients in a Chinese population. The correlation between genotype and survival outcomes was assessed by the Kaplan–Meier method, Cox proportional hazards models and the log-rank test. Our results revealed that individuals with CASP8 −652 6N ins/del + del/del genotypes had a decreased risk of death compared with those with ins/ins genotype (log-rank P = 0.005; hazard ratio = 0.75, 95% confidence interval = 0.62–0.92). The protective effect of the del allele was further confirmed in subgroups of patients with tumor size ≤5 cm (0.66, 0.50–0.86) and T2 depth invasion (0.59, 0.37–0.94), but no significant association was observed in the subgroups of lymph node metastasis (0.67, 0.47–0.97), and distance metastasis (0.73, 0.60–0.90). Our findings suggest that, if validated in different independent populations, the CASP8 −652 6N ins > del polymorphism may serve as a promising genetic marker for gastric cancer prognosis. Environ. Mol. Mutagen. 55:421–427, 2014. © 2014 Wiley Periodicals, Inc.